Subunit selectivity of topiramate modulation of heteromeric GABAA receptors

Topiramate (TPM) is an anticonvulsant of novel chemical structure whose mechanism of action remains elusive. Reports of TPM modulation of ligand- and voltage-gated ion channel functions are variable and often inconsistent. In fact, TPM has been found to produce enhancement, inhibition, and no effect on GABA-currents of cultured neurons and GABAA receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABAA receptors, multiple combinations of recombinant GABAA receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the β subunit isoform co-expressed in heteromeric GABAA receptors. TPM potentiated and directly activated heteromeric receptors containing either β2 or β3 subunit. TPM's direct activation was most effective on receptors comprised of α4β3γ2S subunits and activated ∼74% of the peak GABA-current. TPM modulation of β1-containing heteromeric receptors depended on the co-expressed α subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the β subunit present. These results suggest that the effects of TPM on GABAA receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.